9-35093104-A-C

Position:

• chr9-35093104-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032634.4(PIGO):​c.1045T>G​(p.Ser349Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S349L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIGO NM_032634.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.630

Genes affected

PIGO (HGNC:23215): (phosphatidylinositol glycan anchor biosynthesis class O) This gene encodes a protein that is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor is a glycolipid which contains three mannose molecules in its core backbone. The GPI-anchor is found on many blood cells and serves to anchor proteins to the cell surface. This protein is involved in the transfer of ethanolaminephosphate (EtNP) to the third mannose in GPI. At least three alternatively spliced transcripts encoding two distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10996008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIGO	NM_032634.4	c.1045T>G	p.Ser349Ala	missense_variant	6/11	ENST00000378617.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIGO	ENST00000378617.4	c.1045T>G	p.Ser349Ala	missense_variant	6/11	1	NM_032634.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperphosphatasia with intellectual disability syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 540452). This variant has not been reported in the literature in individuals affected with PIGO-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 349 of the PIGO protein (p.Ser349Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.031	.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.57	.;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.91	L;L;L
MutationTaster	Benign	0.87	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.34	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.095	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.15
MutPred		0.39		Loss of glycosylation at S349 (P = 0.0046);Loss of glycosylation at S349 (P = 0.0046);Loss of glycosylation at S349 (P = 0.0046);
MVP		0.34
MPC		0.12
ClinPred		0.097	T
GERP RS		1.8
Varity_R		0.059
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554673142; hg19: chr9-35093101;